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| United States Patent |
5,342,610
|
|
Katoh
, et al.
|
August 30, 1994
|
Benzophenone derivative, ultraviolet absorbent and external preparation
for skin
Abstract
Benzophenone derivatives expressed by the following general expression (1):
A(C--B).sub.n (1)
wherein A in the above general expression (1) is a residual group obtained
by removing one hydroxyl group from sugar or sugar alcohol, and
B is a benzophenone group shown by the following general expression (2)
##STR1##
wherein R.sub.1 through R.sub.10 each is expressed by hydrogen, hydroxyl
group, an alkoxy group, or the aforesaid binder C, and at least one of
them is the binder C. In the case of an alkoxy group, preferably the
number of carbon atoms is 1 to 4.
C is equivalent to --O--R-- (O is oxygen, R is a fatty chain, and the
number of carbon atoms therein is preferably 1 to 4), or 1 mole of
glycerin with one hydroxyl group therein bound to A and another hydroxyl
group to B. The benzophenone derivatives according to the present
invention have excellent capability to absorb ultraviolet rays as well as
high compatibility with polar solvent. Also the external preparation for
skin in which the benzophenone derivatives are mixed can be mixed in a
polar base with wide availability for industrial purpose.
| Inventors:
|
Katoh; Mikiko (Yokohama, JP);
Uehara; Keiichi (Yokohama, JP);
Takata; Sadaki (Yokohama, JP)
|
| Assignee:
|
Shiseido Co., Ltd. (Tokyo, JP)
|
| Appl. No.:
|
963901 |
| Filed:
|
October 20, 1992 |
Foreign Application Priority Data
| Oct 21, 1991[JP] | 3-301076 |
| Sep 04, 1992[JP] | 4-262962 |
| Current U.S. Class: |
424/59; 424/78.03; 536/18.1 |
| Intern'l Class: |
F61K 007/42; C07H 015/24 |
| Field of Search: |
536/18.1
424/59,78.03
|
References Cited
U.S. Patent Documents
| 3415875 | Dec., 1968 | Luethi et al.
| |
| Foreign Patent Documents |
| 1481633 | Mar., 1966 | FR.
| |
| 2307820 | Mar., 1976 | FR.
| |
| 58-110535 | Jul., 1983 | JP.
| |
| 1186818 | Nov., 1968 | GB.
| |
Other References
Biochim Biophys Acta 946 (1988) 75-84 Holman et al.
|
Primary Examiner: Lilling; Herbert J.
Attorney, Agent or Firm: Townsend & Banta
Claims
What is claimed is:
1. Benzophenone derivative expressed by the following general expression
(1):
A(C--B).sub.n ( 1)
wherein A in the above general expression (1) is a residual group having 4
or more carbon atoms obtained by removing one hydroxyl group from sugar or
sugar alcohol, n is 1 to 3, and
B is a benzophenone group shown by the following general expression (2)
##STR7##
wherein R.sub.1 through R.sub.10 each is expressed by hydrogen, hydroxyl
group, an alkoxy group having 1 to 4 carbon atoms, or the aforesaid binder
C, and at least one of them is the binder C, and
C is --O--R, O is oxygen, R is 1 to 4 carbon atoms, or 1 mole of glycerin
with one hydroxyl group herein bound to A and another hydroxyl group to B.
2. Ultraviolet absorbent contains one or more of the benzophenone
derivatives according to claim 1.
3. External preparation for skin contains one or more of benzophenone
derivatives according to claim 1.
4. Benzophenone derivatives expressed by the following general expression
(3):
A(C--B).sub.n ( 3)
wherein A in the above general expression (3) is a residual group having 4
or more carbon atoms obtained by removing one hydroxyl group from sugar or
sugar alcohol, and
B is a benzophenone group shown by the following general expression (4);
##STR8##
wherein at one of R.sub.1 through R.sub.9 in the general expression (4) is
a group bound C, and the others are hydrogen, an alkyl group, or an alkoxy
group;
C is equivalent to 1 mole or glycerin with one hydroxyl group therein bound
to A and another hydroxyl group to B; and
n is 1 to 3.
5. Ultraviolet absorbent contains one or more of the benzophenone
derivatives according to claim 4.
6. External preparation for skin contains one or more of benzophenone
derivatives according to claim 4.
7. Benzophenone derivatives expressed by the following general expression
(7):
##STR9##
wherein R.sub.1 and R.sub.2 each is hydrogen or hydroxyl group, and at
least one of them is expressed by a hydroxyl group;
R.sub.3 to R.sub.10 each is hydrogen, a hydroxyl group, or --O--R--A and at
least one of them is expressed by the --O--R--A, in case of an alkoxy
group, the number of carbon atoms is 1 to 4,
A is a residual group obtained by removing one hydroxyl group from sugar,
and
R is 1 to 4 carbon atoms.
8. Ultraviolet absorbent contains one or more of the benzophenone
derivatives according to claim 7.
9. External preparation for skin contains one or more of benzophenone
derivatives according to claim 7.
Description
FIELD OF THE INVENTION
This invention relates to a benzophenone derivative, an ultraviolet
absorbent and an external preparation for skin or more particularly, a
benzophenone derivative having a high solubility in water, and an
ultraviolet absorbent and an external preparation for skin using the
benzophenone derivative.
BACKGROUND OF THE INVENTION
Most of ultraviolet ray normally received by a human body comes from
sunlight. The ultraviolet ray included in sunlight is divided to a long
wavelength ultraviolet ray having a wavelength from 400 nm to 320 nm
(UV-A), a medium wavelength ultraviolet ray having a wavelength from 320
nm to 290 nm (UV-B), and a short wavelength ultraviolet ray having a
wavelength of not more than 290 nm in a field of skin science. Of these,
the ultraviolet rays having a wavelength of not more than 290 nm are
absorbed by the ozonosphere and does not reach the surface of the earth.
The ultraviolet rays reaching the surface of the earth give various
influences to human skin. Of the ultraviolet rays reaching the surface of
the earth, the UV-A makes color of human skin brown, reduces the
elasticity of skin, and promote generation of wrinkles, thus causing rapid
aging of human skin. Also the ultraviolet rays promote start of the
erythema reaction, or further stimulates this reaction in certain types of
patients, and furthermore sometimes may cause photo-toxicity or photo
allergy reactions. On the other hand, also UV-B forms erythema or blister
on human skin, and causes aggravation of melanin formation or other
changes such as deposition of pigments.
For the reasons as described above, in order to prevent aging of human skin
and generation or increase of wrinkles and flecks thereon, it is very
important to protect human skin from the ultraviolet rays, and various
types of ultraviolet absorbent have been developed for that purpose.
The existing ultraviolet absorbents used for practical application include
a PABA derivative, a cinnamic acid derivative, a salicylic acid
derivative, a benzophenone derivative, a urocanine derivative, a campher
derivative, and heterocyclic derivatives.
These types of ultraviolet absorbent are generally mixed in external
preparations for skin such as cosmetics, or quasidrugs, and a low
molecular weight dimethyl-siloxane base has been widely used as a base for
the external preparation for skin.
Namely, as anti-suntan agent are most frequently used during summer, oily
bases have been used because of their anti-sweat property as well as their
high water resisting property, and as a result, most of materials which
have been used for ultraviolet absorbents are oil soluble.
Recently, however, social attention has been focused on effects of
ultraviolet rays on human skin in our daily life, so that anti-suntan
materials are desired for ordinary skin care. For that purpose,
development of materials which are water soluble and at the same time
absorb ultraviolet rays has been strongly demanded, because such materials
can mixed in aqueous external preparation such as skin lotion in a large
volume, and also because a large volume of ultraviolet absorbent is
required to be mixed in the entire system to realize a external
preparations having the high capability to absorb ultraviolet rays, which
makes it necessary to mix a ultraviolet absorbent not only in oil phase
but also in aqueous phase.
The prior types of ultraviolet absorbent, however, are oil soluble in most
cases, and their solubility in water is very low, and their applications
have been limited to a relatively narrow area. As a water soluble
ultraviolet absorbent, only 2-hydroxy-4-methoxy-5-sulfoxonium benzophenone
sodium salt has been known, and as this is a salt, it effects pH of the
formula system.
DISCLOSURE OF THE INVENTION
This invention was made to solve the problem in the prior art as described
above, and the object is to provide a water soluble material having a high
ultraviolet absorptivity and an external preparation for skin in which the
material is mixed.
The invention made strenuous efforts to achieve the object as described
above, and found that a certain benzophenone derivative had an ultraviolet
absorptivity as well as a compatibility with polar solvent, thus
completing the present invention.
The benzophenone derivative described in the claim 1 in the present
application is expressed by the following general expression (1),
A(C--B).sub.n ( 1)
In the general expression (1) above, A is a residual group obtained by
removing a hydroxyl group from sugar or sugar alcohol, while B is a
benzophenone group which is expressed by the following general expression
(2).
##STR2##
wherein each of R.sub.1 to R.sub.10 are expressed by hydrogen, a hydroxyl
group, alkoxy group, or the aforesaid binder C, and at least one of them
is a binder C. In case of an alkoxy group, the number of carbon atoms is
preferably in a range from 1 to 4.
C is --O--R-- (O is oxygen, while R is a fatty chain preferably having 1 to
4 carbon atoms), or 1 mole of glycerin. In case of glycerin, one of the
hydroxyl groups is bound to A and another hydroxyl group is bound to B.
n is 1 or other integer.
The ultraviolet absorbent described in the claim 2 is characterized in that
at least one type of benzophenone derivatives expressed by the general
expression (1) above are included therein.
The external preparation for skin described in the claim 3 is characterized
in that at least one of the benzophenone derivative expressed by the
general expression (1) above are included therein.
Also, the benzophenone derivative described in the Claim 4 in the present
application is expressed by the following general expression (3).
A(C--B).sub.n ( 3)
Herein, A is sugar or sugar alcohol, C is 1 mole of glycerin wherein one of
the hydroxyl groups is bound to A and another hydroxyl group is bound to
B.
B is a benzophenone group expressed by the following general expression
(4).
##STR3##
(In the general expression (4), at least one of R.sub.1 through R.sub.g is
a group bound to C, and others are hydrogen or a hydroxyl group, an alkyl
group, or an alkoxyl group.
n or other integer.
The ultraviolet absorbent described in the Claim 5 is characterized in that
at least one type of the benzophenone derivatives expressed by the general
expression (3) above is included therein.
The external preparation for skin described in Claim 6 is characterized in
that at least one of the benzophenone derivatives expressed by the general
expression (3) above is included.
In the general expression (3) above, A is a residual group of sugar or
sugar alcohol, and examples of the sugar include mono saccharides such as
glucose, galactose, xylose, fructose, altose, talose, mannose, arabinose,
idose, lyxose, ribose, allose, gulose, erythrose, threose, tagatose,
sorbose, psicose, xylulose, ribulose, erythrulose, fucose, rhamnose and a
mixture thereof; disaccharide such as maltose, isomaltose, lactose,
xylobiose, gentiobiose, kojiobiose, cellobiose, sohorose, nigerose,
sucrose, melibiose, laminaribiose, rutinose, lactulose, palatinose,
turanose, trehalose and a mixture thereof; or trisaccharides such as
maltotriose, meleziose, raffinose and a mixture thereof; furthermore
higher polysaccharide and a mixture thereof; and also a mixture of the
monosacchride, disaccharide, and higher polysaccharide can be used for
this purpose. On the other hand, examples of sugar alcohol include sugar
alcohol such as maltitol, sorbitol, mannitol, galactitol, glucitol,
inositol, maltitriol, threitol, arabinitol, alcritol and a mixture
thereof, or higher polysaccharide and a mixture thereof, and also a
mixture of these sugar alcohol can be used for this purpose. Furthermore,
the same effect can be achieved by using a mixture of the monosaccharide,
disaccharide, higher polysaccharide, and sugar alcohol.
In the general expression (4) which expresses a benzophenone group B, each
of R.sub.1 to R.sub.9 expresses a bond group to hydrogen or hydroxyl
group, an alkyl group or an alkoxyl group, or a bond group to C. In case
of an alkyl group or an alkoxyl group, the fatty chain may be any of a
straight chain alkyl group, a branch chain alkyl group, an unsaturated
alkyl group and a cycloalkyl group, and example of the fatty chain include
a methyl group, an ethyl group, an acetynyl group, a propyl group, an
isopropyl group, a propenyl group, a butyl group, an isobutyl group, a
t-butyl group, and a butenyl group. Wavelength of absorbed ultraviolet
rays does not differ remarkably in any case, but a methyl group and a
ethyl group are especially preferable because of their industrial
applicability.
C is a glyceril group which is equivalent to 1 mole of glycerin, and any
form of bond may be added.
n indicates an integer, and preferably indicates any of 1 to 3 because of
the water solubility.
As the benzophenone derivatives described above are in solid or syrupy
state and are extremely excellent in their safety and stability, the
materials can be mixed in chemical products such as dye or ink, plastics,
coating agent, and chemical textile, and in addition they can be mixed in
pharmaceutical products, quasidrug products, cosmetics and cleaning agents
as a component. Furthermore, the materials feature the excellent
capability to preserve humidity.
The benzophenone derivative expressed by the general expression (3) can be
produced by, for instance, glycydilating hydroxy benzophenone expressed by
the general expression (5) and reacting the resultant glycidyloxy
benzophenone expressed by the general expression (6) with sugar or sugar
alcohol according to the method described in the Japanese Patent
Application No. 180989/1986.
##STR4##
For instance, the derivative can be synthesized as follows.
The compound expressed by the general expression (6) can be synthesized by
reacting the compound expressed by the general expression (5) according to
the method developed by Sandlere et. al., (S. R. Sandler, F. R. Berg, J.
Appl. Polymer. Soc. 9,3707(1965)), or according to the method developed by
Robert et. al., (Tetrhedorn, 35, 2169-2172 (1979)). Namely, the compound
expressed by the general expression (6) can be synthesized by dissolving
or suspending the compound expressed by the general expression (5) in a
non-aqueous solvent such as dimethylsulfoxide, dimethylformamide, dioxan,
dimethylacetamide, N-methylpyrrolidone, N-acctylmorpholine, N-methyl
succinic acid imid, or by dissolving or suspending the compound expressed
by the general expression (5) in acetone aqueous solvent, or by mixing the
compound expressed by the general expression (5) with epichlorohydrin
under the temperature from 90.degree. to 130.degree. C. in the presence of
a catalyst without using any solvent. This reaction may be carried out
under flow of such a gas as argon, and one or more compounds expressed by
the general expression (5) may be used in this reaction.
The catalysts available in this reaction include a Lewis Acidic Catalyst
such as BF.sub.3 .multidot.Et.sub.2 O or aluminum trichloride; acidic
catalyst such as p-toluene sulfonic acid, heteropoly phosphoric acid,
chloric acid, sulfuric acid; alkali such as sodium hydroxide, potassium
hydroxide, potassium carbonate, sodium carbonate, sodium hydride, sodium
alcoholate; and amine such as N-methylbenzyl amine.
The compound expressed by the general expression (3) can be manufactured by
reacting the compound expressed by the general expression (4) to sugar or
sugar alcohol according to, for instance, the method described in Japanese
Patent Application No. 180989/1986.
For instance, the following method is applicable. Sugar or sugar alcohol
may be dissolved or suspended in a non-aqueous solvent such as
dimethylsulfoxide, dimethylformamide, dioxan, dimethylacetamide,
N-Methylpyrrolidone, N-acetylmorpholine, or N-methylsuccinimid, and mixed
and stirred with the compound expressed by the general expression (6)
under the temperature from 90.degree. to 130.degree. C. in the presence of
a catalyst. This reaction may be carried out under a flow of gas such as
N.sub.2 or argon, and also one or more compounds expressed by the general
expression (6) may be used in this reaction.
The catalysts available in this reaction include a acidic catalyst such as
p-toluene sulfonic acid, heteropoly phosphoric acid, chrolic acid, or
sulfonic acid; alkali catalyst such as sodium hydrate, potassium hydrate,
potassium carbonate, sodium carbonate, sodium alcoholate; salt such as
ammonium chloride, or sodium chloride; and amine such as
N-methylbenzylamine.
The mole ratio of sugar or sugar alcohol vs. the compound expressed by the
general expression (6) to be used in this reaction should preferably be
1:1 to 3:1 when it is necessary to obtain monoether as a main product, and
more preferably be in a range from 2:1 to 3:1. If the mole ratio of sugar
or sugar alcohol and the compound expressed by the general expression (6)
is out of the ranges described above; namely if sugar or sugar alcohol is
too little, impurities such as tetraether would be easily generated, and
if sugar or sugar alcohol is too much, a large volume of the material
would remain after the reaction, which affects purification of the
product, and it is not preferable.
When acid or alkali is used as a catalyst, acid such as acetic acid,
chloric acid, sulfuric acid, or phosphoric acid, or alkali such as sodium
hydrate or potassium hydrate should be added to neutralize the catalyst in
the reaction system after all of the compound expressed by the general
expression (6) is consumed.
After the reaction as described above, the reactant solvent may be
depressurized and removed, the product may be used as it is or may be
diffused in a solvent for use, or may be purified according to the column
chromatography or the recrystalizing method.
In the resultant product obtained as described above, in addition to the
benzophenone expressed by the general expression (3), compounds wherein n
in the general expression (3) is 4 or more, salt, sugar or sugar alcohol
not reacted yet may coexist. For this reason, in order to remove the sugar
or sugar alcohol or salt therefrom, the product may be purified by
extracting with a solvent such as methyl alcohol, ethyl alcohol, butyl
alcohol, isopropyl alcohol, or by diffusing it in a mixture of water and
methylethyl ketone having a large volume of salt therein and fractionating
the organic solvent layer. Also in order to remove sugar or sugar alcohol
and salt for separating the compound, the resultant product may be
purified by dissolving or suspending the resultant product in water or a
mixture of water and alcohol, passing it at first through water in a
opposite phase partition column such as hyper porous polymer (such as
Hi-porous resin supplied from Mitsubishi Kasei Kogyo Kabushiki Kaisha) or
octadecyl silica, and then through a mixed solution of water with alcohol
such as methanol or ethanol or a polar organic solvent such as
acetonitrile, and fractionating and taking out this liquid. Also the
resultant product can be purified in an ordinary phase system according to
the silica gel chlomatograph or other appropriate method.
By the way, it is preferable to use a ultraviolet absorbent in the form of
aqueous solution in which a non-ionic hydrophilic group has been
introduced for the purpose to reduce its effect over pH of the entire
reaction system. As a non-ionic hydrophilic group, mainly polyethylene
oxide, polyglycerin, or sugar can be considered. Of these, polyethylene
oxide is decomposed as time goes by and generates formalin, and dioxan is
contained in it, so recently the material is regarded as not preferable
for safety. From this point of view, polyglycerin or sugar is preferable
because the safety is very high. On the other hand, it is desired that the
base consists of a single components, but polyethylene oxide or
polyglycerin is apt to form a mixture having inhomogenious distribution
because of the characteristics in the systhesizing reaction for the
materials, and also purification of the material is not so easy. In
contrast to it, products of a hydrophilic group such as sugar are hard to
form a mixture, and also the purification is easy, so that it is
preferable.
However, in such processes as direct etherification or direct
esterification of sugar, also a mixture having distributed mole numbers of
added components is easily generated, which is troublesome.
So the inventors further developed the following benzophenone derivative to
solve the problems as described above.
Namely, the benzophenone derivative described in the Claim 7 in this
application is expressed by the following general expression (7),
##STR5##
wherein R.sub.1 and R.sub.2 are hydrogen or hydroxyl group, and at least
one of them is expressed by a hydroxyl group.
R.sub.3 through R.sub.10 are expressed by hydrogen, a hydroxyl group, an
alkoxy group, or --O--R--A, and at least one of them is expressed by
--O--R--A. In case of an alkoxy group, preferably the number of carbon
atoms is in a range from 1 to 4. A is a residual group obtained by
removing one hydroxyl group from sugar, R is a fatty chain, and preferably
the total number of carbon atoms is in a range from 1 to 4.
The ultraviolet absorbent described in the Claim 8 is characterized in that
said ultraviolet absorbent contains one or more types of benzophenone
derivatives expressed by the aforesaid general expression (7).
The external preparation for skin described in the Claim 9 is characterized
in that said external preparation contains one or more types of
benzophenone derivatives expressed by the aforesaid general expression
(7).
In the general expression (7) above, A is a residual group of sugar, and
examples of the sugar include monosaccharide such as glucose, galactose,
xylose, fructose, altrose, talose, mannose, arabinose, idose, lyxose,
ribose, allose, gulose, erythrose, threose, tagatose, sorbose, psicose,
xylulose, ribulose, erythrulose, fucose, rhamnose and a mixture thereof;
disaccharide such as maltose, isomaltose, lactose, xylobiose, gentiobiose,
kojiobiose, cellobiose, sohorose, nigerose, sucrose, melibiose,
laminaribiose, rutinose, lactulose, palatinose, turanose, trehalose and a
mixture thereof; or trisaccharides such as maltotriose, meleziose,
raffinose and a mixture thereof; furthermore higher polysaccharide and a
mixture thereof, disaccharide, and higher polysaccharide can be used for
this purpose.
In R.sub.3 through R.sub.10, if O--R--A is used, the fatty chain as R may
be any of a straight chain alkyl group, a branch chain alkyl group, an
unsaturated alkyl group, and a cycloalkyl group, and example of the fatty
chain include a methyl group, an ethyl group, an acetynyl group, a propyl
group, an isopropyl group, a propenyl group, a butyl group, an isobutyl
group, a t-butyl group, a butenyl group. Wavelength of absorbed
ultraviolet rays does not differ remarkably in any case, but a methyl
group and a ethyl group are especially preferable because of their
industrial applicability. Also, in R.sub.3 to R.sub.10, if an alkoxy group
is used, also a fatty chain in said alkoxy group may be any of a straight
chain alkoxy group, a branch chain alkoxy group, an unsaturated alkoxy
group, and a cycloalkoxy group, and examples include a methoxy group, an
ethoxy group, a acetoxy group, a propyroxy group, an isopropyroxy group, a
propenyloxy group, a butyloxy group, an isobutyloxy group, a t-butyroxy
group, and a bytenyloxy group. Wavelength of absorbed ultraviolet rays in
any of the compounds above does not differ remarkably, but especially the
methoxy group and the ethoxy group are preferable because of their high
solubility in water or excellent applicability for industrial purpose.
The benzophenone derivatives are in solid state and are extremely excellent
in their safety and stability, so the materials can be mixed in chemical
products such as dye or ink, plastics, coating agents, and chemical
textiles, and in addition they can be mixed as components in
pharmaceutical products, quasidrug products, cosmetics, and cleaning
agents.
The benzophenone derivatives relating to the general expression (7) can be
synthesized by using the acidic catalyst for denaturing sugar described in
the Japanese Patent Laid Open Publication No. 84637/1988, or through a
reaction generally used for glycosylation (such as Kenich-Knol reaction,
Helferich method, or other ether exchanging method).
For instance, the benzophenone derivatives relating to the general
expression (7) above can be synthesized as follows.
To obtain the above materials, acetylate of sugar is dissolved in a
non-polarized solvent such as dibutyl cellosolve or toluene, or a compound
expressed by the general expression (8)
##STR6##
(wherein R.sub.1 and R.sub.2 are the same as the aforesaid compounds (2)
above, R'.sub.3 through R'.sub.10 are expressed by hydrogen, hydroxyl
group, an alkoxy group, or O--R--OH, and at least one of them is expressed
by O--R--OH. The number of carbon atoms in the alkoxy group is preferably
from 1 to 4, and R is a fatty chain having 1 to 4 carbon atoms) is added
and stirred under the temperature from 90.degree. to 130.degree. C. in the
presence of a acidic catalyst. The reaction is carried out in a
depressurized state, and 2 or more compounds expressed by the general
expression (8) may be used in this reaction.
The catalysts available in this reaction include p-toluene sulfonic acid,
heteropoly phosphoric acid, zinc acetate, zinc chloride, or ion-exchange
resin.
After the reaction, the reactant solvent is distillated under reduced
pressure condition for removal and the product is extracted with toluene,
and then washed with water. The resultant extracted liquid may be
condensed under reduced pressure condition and then deacetylated as it is
or may be purified according to the silica gel column chromatography and
then deacetylated.
In the resultant product thus obtained, in addition to the benzophenone
derivatives expressed by the general expression (7), salt generated when
neutralized, sugar and other materials coexist. For this reason, in order
to remove, for instance, sugar and salt, the product can be purified by
extracting it with a solvent which does not dissolve sugar such as methyl
alcohol, ethyl alcohol, butyl alcohol, or isopropyl alcohol, or by
diffusing it in a mixture of water containing a large volume of sugar,
methylethyl ketone, and n-bythanol and fractionating the organic solvent
layer. Also in order to remove sugar or sugar alcohol and salt for
separating the compound, the resultant product may be purified by
dissolving or suspending the resultant product in water or a mixture of
water and alcohol, passing it at first through water in a opposite phase
partition column such as hyper porous polymer (such as Hi-porous resin
supplied from Mitsubishi Kasei Kogyo Kabushiki Kaisha) or octadecyl
silica, and then through a mixed solution of water with alcohol such as
methanol or ethanol, or polar organic solvent such as acetonitrile, and
fractionating and taking out this liquid.
The benzophenone derivatives as described above may be used after the
solvent for extraction is removed by means of distillation under reduced
pressure condition or purified using a column, or may be used as it is.
The benzophenone derivatives thus obtained are excellent in their chemical
stability and resistance against oxidation, and are also water soluble and
can absorb ultraviolet rays in a wide range, and furthermore they are
excellent in their capability to preserve humidity. As the benzophenone
according to the present invention are excellent in their stability, the
materials can be mixed in cosmetics or pharmaceutical drugs. In addition
to the embodiments of the present invention, the materials can
appropriately be mixed with other ordinary cosmetics and other components
for pharmaceutical drugs. For instance, various types of hydro carbon such
as fluidized paraffin, squalane, vaseline, cetyl alcohol, isostearyl
alcohol, 2-ethyl hexanoic acid cetyl, 2-octyldodecyl alcohol,
triisostearic acid glycerin, Macademian nuts oil, and lanolin; fats and
oils, oily components such as wax, silicone, surface active agents,
thickeners, neutralizers, antiseptics, germicides, anti-oxidants, powder
components, perfumes, other ultraviolet absorbents, drugs, metallic
sealant, and pH modifiers can be listed as such materials.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a chart of an infrared absorption spectrum of 1-(4-benzoylphenyl)
glycerol maltitolether according to an embodiment of the present
invention;
FIG. 2 is a chart of .sup.13 C-NMR spectrum of 1-(4-benzoylphenyl) glycerol
maltitolether according to an embodiment of the present invention;
FIG. 3 is a chart of .sup.1 H-NMR spectrum of 1-(4-benzoylphenyl) glycerol
maltitolether according to an embodiment of the present invention;
FIG. 4 is a chart of ultraviolet absorption spectrum of 1-(4-benzoylphenyl)
glycerol maltitolether according to an embodiment of the present
invention;
FIG. 5 is a chart of an infrared absorption spectrum of
1-(4-benzoyl-3-hydroxy-phenyl) glycerol maltitolether according to an
embodiment of the present invention;
FIG. 6 is a chart of .sup.13 C-NMR spectrum of
1-(4-benzoyl-3-hydroxy-phenyl) glycerol maltitolether according to an
embodiment of the present invention;
FIG. 7 is a chart of .sup.1 H-NMR spectrum of
1-(4-benzoyl-3-hydroxy-phenyl) glycerol maltitolether according to an
embodiment of the present invention;
FIG. 8 is a chart of ultraviolet absorption spectrum of
1-(4-benzoyl-3-hydroxy-phenyl) glycerol maltitolether according to an
embodiment of the present invention;
FIG. 9 is a chart of an infrared absorption spectrum of
2-hydroxy-4-(2-maltosiloxyethoxy) benzophenone according to an embodiment
of the present invention;
FIG. 10 is a chart of .sup.13 C-NMR spectrum of
2-hydroxy-4-(2-maltosiloxyethoxy) benzophenone according to an embodiment
of the present invention;
FIG. 11 is a chart of .sup.1 H-NMR spectrum of
2-hydroxy-4-(2-maltosiloxyethoxy) benzophenone according to an embodiment
of the present invention;
FIG. 12 is a chart of ultraviolet absorption spectrum of
2-hydroxy-4-(2-maltosiloxyethoxy) benzophenone according to an embodiment
of the present invention;
FIG. 13 is a chart of an infrared absorption spectrum of
2-hydroxy-4-(2-glucosiloxyethoxy) benzophenone according to an embodiment
of the present invention;
FIG. 14 is a chart of .sup.13 C-NMR spectrum of
2-hydroxy-4-(2-glucosiloxyethoxy) benzophenone according to an embodiment
of the present invention;
FIG. 15 is a chart of .sup.1 H-NMR spectrum of
2-hydroxy-4-(2-glucosiloxyethoxy) benzophenone according to an embodiment
of the present invention;
FIG. 16 is a chart of ultraviolet absorption spectrum of
2-hydroxy-4-(2-glucosiloxyethoxy) benzophenone according to an embodiment
of the present invention;
FIG. 17 is a chart of an infrared absorption spectrum of
2-hydroxy-(3-maltosiloxypropyloxy) benzophenone according to an embodiment
of the present invention;
FIG. 18 is a chart of .sup.13 C-NMR spectrum of
2-hydroxy-(3-maltosiloxypropyloxy) benzophenone according to an embodiment
of the present invention;
FIG. 19 is a chart of .sup.1 H-NMR spectrum of
2-hydroxy-(3-maltosiloxypropyloxy) benzophenone according to an embodiment
of the present invention;
FIG. 20 is a chart of ultraviolet absorption spectrum of
2-hydroxy-(3-maltosiloxypropyloxy) benzophenone according to an embodiment
of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Description is made hereinafter for preferred embodiments of the present
invention. It should be noted that the embodiment are not intended to
limit the scope of the present invention. A unit for mixing rate is weight
%.
Embodiment 1 1-(4-benzoylphenyl) glycerol maltitolether
1 g of 4-hydroxy benzophenone and 4.668 g of epichlorohydrin (0.025 mol)
were dissolved, 20.5 mg of sodium hydroxide was added, and the reaction
system was heated to 100.degree. C. and then cooled to 95.degree. C.
Furthermore 201.4 mg of sodium hydroxide was added, and additional heating
and agitation was carried out for 3 hours. The system was cooled to the
room temperature, and salt was removed by filtering. The obtained filtrate
was condensed under reduced pressure condition, and purified according to
the silica gel chromatography to obtain 1.0 g of solid state 4-glycidyloxy
benzophenone (Yield: 83%).
Then, 2.921 g of maltitol and 476.0 mg of potassium hydroxide were
dissolved in 20 ml of dimethylsulfoxide, and the mixture was stirred under
flow of nitrogen for 30 minutes. A solution obtained by dissolving 719 mg
of the resultant 4-glycidyloxy benzophenone dissolved in 1 ml of
dimethylsulfoxide was dripped to it. Furthermore, heating and agitation
was continued for 1 hour under flow of nitrogen, and the reaction system
was cooled to the room temperature and neutralize with chloric acid. The
reaction system was fractionated according to the column chromatography
using the hyperporous polymer (Hiporous resin supplied from Mitsubishi
Kasei Kogyo Kabushiki Kaisha) at first as a developing solvent with
purified water, and then a mixture of ethyl alcohol and purified water
with the mixing ratio of 1:1, and effluent fraction in which the mixing
ratio of ethyl alcohol and purified water was 1:1 was condensed to
obtained 500 mg of 1-(4-benzoylphenyl) glycerol maltitolether (Yield:
30%).
(1) Infrared absorption spectroscopy
Measurement was made by using the IRA-1 infrared absorption spectrometer
supplied from Nihon Bunko Kabushiki Kaisha with the KBr disk method, and
absorption due to stretching vibration of the hydroxyl group at 3387
cm.sup.-1, stretching vibration of the glyceroil group at 2928 cm.sup.-1
and stretching vibration of the carbonyl group at 1649 cm.sup.-1 were
observed.
The results are shown in FIG. 1.
(2) .sup.13 C-NMR spectroscopy
Measurement was made by using CD.sub.3 OD as a solvent with JOEL GX-400
supplied from Nippon Denshi Kabushiki Kaisha at 35.degree. C., and signal
from carbon atoms in the benzophenone part was observed at .delta.197 ppm,
164 ppm, 139 ppm, 134 ppm, 133 ppm, 131 ppm, 129 ppm, and 115 ppm, and
signals from the maltitol group and the glyceril group was observed in a
range from 103 ppm to 62 ppm.
The results are shown in FIG. 2.
(3) .sup.1 H-NMR spectroscopy
Measurement was made by using CD.sub.3 OD as a solvent with JOEL GX-400
supplied from Nippon Denshi Kabushiki Kaisha under room temperature, and
signals from hydrogen in the benzophenone section were observed in the
range of .delta.7.8-7.1 ppm and signal from hydrogen in the maltitol group
and glyceril group were observed in the range of .delta.5.2-3.3 ppm.
The results are shown in FIG. 3.
(4) Ultraviolet ray absorption spectroscopy
Measurement was made by using the UVIDEC 610 C ultraviolet ray absorption
spectrometer from Nihon Bunko Kabushiki Kaisha with methanol as a solvent,
and the peak absorption was observed at 282.7 nm.
The results was shown in FIG. 4.
(5) Phenol indication
The product was spotted on TCL, phenol indicator was sprayed with a sprayer
on it. 10% sodium carbonate solution was sprayed over it, but a color
indicating presence of phenol was not observed.
Embodiment 2 1-(4-benzoyl-3-hydroxyphenyl) glycerolmaltitolether
3.0 g of 2,4-dihydroxy benzophenone and 15.5 g of epichlorohydrin (0.075
mol) were dissolved, and 112.0 mg of sodium hydroxide was added. The
reaction system was heated to 100.degree. C. and then cooled to 95.degree.
C., and 672.2 mg of sodium hydroxide was added. Additional heating and
agitation was continued for 3 hours. Then, the reaction system was cooled
to the room temperature, and salt was removed by filtering. The resultant
filtrate was condensed under reduced pressure condition, and purified
according to the silica gel column chromatography. 2.8216 g of solid state
4-glycidyloxy-2-hydroxy benzophenone was obtained (Yield: 75%).
Then, 1.550 g of maltitol and 84.2 mg of potassium hydroxide were dissolved
in 10 ml of dimethylsulfoxide. The mixture was heated and stirred for 30
minutes under a flow of nitrogen, and a solution obtained by dissolving
406.0 mg of 4-glycidyloxy-2-hydroxy benzophenone in 6 ml of
dimethylsulfoxide was dripped to it. Then, heating and agitation under
flow of nitrogen was carried out for 1 hour, and then the reaction system
was cooled to the room temperature and the mixture was neutralized by
chloric acid. The reaction system was fractionated according to the column
chromatography using the hyperporous polymer (Hiporous resin supplied from
Mitsubishi Kasei Kogyo Kabushiki Kaisha) at the first time as a solvent
with purified water, and then a mixture of ethyl alcohol and purified
water with the mixing ratio of 1:1. Effluent fraction in which the mixing
ratio of ethyl alcohol and purified water was 1:1 was condensed to obtain
478 mg of 1-(4-benzoyl-3-phenyl)glycerol maltitolether (Yield: 52%).
(1) Infrared absorption spectroscopy
Measurement was made by using the IRA-1 infrared absorption spectrometer
supplied from Nihon Bunko Kabushiki Kaisha with the KBr disk method, and
absorption due to stretching vibration of the hydroxyl group at 3380
cm.sup.-1, stretching vibration of the hydrocarbon group at 2928 cm.sup.-1
and stretching vibration of the carbonyl group at 1626 cm.sup.-1 were
observed.
The results are shown in FIG. 5.
(2) .sup.13 C-NMR spectroscopy
Measurement was made by using CD.sub.3 OD as a solvent with JOEL GX-400
supplied from Nippon Denshi Kabushiki Kaisha at 35.degree. C., and signal
from carbon atoms in the benzophenone part was observed at .delta.201 ppm,
166 ppm, 139 ppm, 136 ppm, 133 ppm, 132 ppm, 130 ppm, 129 ppm and 114 ppm,
and those from the carbons in the maltitol group and the glyceril group
was observed in a range from 109 ppm to 62 ppm.
The results are shown in FIG. 6.
(3) .sup.1 H-NMR spectroscopy
Measurement was made by using CD.sub.3 OD as a solvent with JOEL GX-400
supplied from Nippon Denshi Kabushiki Kaisha, and signals from hydrogen in
the benzophenone section were observed at .delta.12.5 ppm and in the range
of .delta.7.8-7.1 ppm, and signal from hydrogen in the maltitol group and
glyceril group were observed in the range of .delta.5.2-3.3 ppm.
The resultant are shown in FIG. 7.
(4) Ultraviolet ray absorption spectroscopy
Measurement was made by using the UVIDEC 610 C ultraviolet ray absorption
spectrometer from Nihon Bunko Kabushiki Kaisha with methanol as a solvent,
and the peak absoption was observed at 279.8 nm.
The results was shown in FIG. 8.
(5) Phenol indication
The product was spotted on TCL, phenol indicator was sprayed with a sprayer
on it. 10% sodium carbonate solution was sprayed over it, and a color
indicating presence of phenol was observed.
Embodiment 3 4,4'-maltitoiloxyglyceroxy-2,2'hydroxy benzophenone
3.0 g of 2,2',4,4'-tetrahydroxy benzophenone and 31.1 g (0.075 mol) of
epichlorohydrin were dissolved, and 2240.0 mg of sodium hydroxide was
added to it. The reaction system was heated to 100.degree. C. and then
cooled to 95.degree. C., and 1.34 g of the sodium hydroxide was added.
Additional heating and agitation were continued for 3 hours. Then the
system was cooled to the room temperature, and salt was removed by
filtering. The obtained filtrate was condensed under reduced pressure
condition and purified according to the silica gel chromatography. 3.21 g
of 4,4'-diglycidyloxy-2,2'-hydroxy benzophenone in solid state was
obtained.
Then, 1.550 g of maltitol and 84.2 mg of potassium hydroxide were dissolved
in 10 ml of dimethylsulfoxide, and heating and agitation were carried out
for 30 minutes. A solution obtained by dissolved 606.0 mg of
4,4'-diglycidyloxy-2,2'-hydroxy benzophenone in 7 ml of dimethylsulfoxide
was dripped. Furthermore, heating and agitation were continued for 1 hour
under flow of nitrogen. The reaction system was cooled to the room
temperature, and neutralized by chloric acid. The reaction system was
fractionated according to the column chromatography using the hyperporous
polymer (Hiporous resin supplied from Mitsubishi Kasei Kogyo Kabushiki
Kaisha) with at first purified water as a developed solvent and then ethyl
alcohol and purified water in which the mixing ratio of ethyl alcohol and
purified water was 1:1. The effluent section in which the mixing ratio of
ethyl alcohol and purified water was 1:1 was condensed, and 780 mg of
4,4'-maltitoiloxyglyceroxy-2,2'-hydroxybenzophenone was obtained.
Experiment 1 Production of Skin Lotion
According to the formulation as shown in table 1, a skin lotion in which
the benzophenone derivative was mixed, and a skin lotion in which
2-hydroxy-4-methoxy-5-sulfoxisonium benzophenone as a control were
produced.
TABLE 1
______________________________________
COMPONENT EXAMPLE 1 CONTROL 1
______________________________________
A. (ALCOHOL PHASE)
Ethanol 5.0 5.0
POE oleil alcohol ether
2.0 2.0
Perfume q.s. q.s.
B. (AQUEOUS PHASE)
1,3-butylene glycerol
5.0 5.0
Benzophenone derivative
8.0 --
(Embodiment 1)
2-hydroxy-4-methoxy-sulfoxonium
-- 8.0
benzophenone
Triethanol amine 0.1 0.1
Carboxy vinyl polymer
0.15 0.15
Purified water Residual Residual
______________________________________
Alcohol phase A was added to aqueous phase B, and a perfume was made water
soluble to obtain a skin lotion.
In example 1, a skin lotion which has not color and is transparent with
viscosity was obtained, while in control 1 a lotion which was yellow color
and has no viscosity was obtained.
Experiment 2 Test for Anti-suntan Material
Field test were carried out in a sea beach using 2 types of skin lotion
produced in Experiment 1. In the experiment, the sample were applied to
right and left halves of each member of a group consisting of 20 men and
20 women. A degree of sun burning degree was determined. The criteria for
the determination was as follows.
______________________________________
Criteria for evaluation of sun-burning degree
______________________________________
Remarkable erythema recognized
.times.
Slight erythema recognized
.DELTA.
Erythema not recognized
.largecircle.
______________________________________
The results are shown in Table 2.
TABLE 2
______________________________________
APPLIED APPLIED
SECTION IN
SECTION IN
EXAMPLE 1 CONTROL 1
______________________________________
.largecircle.
37 6
.DELTA. 3 12
.times. 0 22
NUMBER OF NONE ITCH 10 CASES
SKIN TROUBLE ERUPTION 2 CASES
CASES
______________________________________
From the results as described above, the external preparation for skin in
which the benzophenone derivative is mixed is more effective for
protection from ultraviolet rays than that in which the prior types of
water soluble ultraviolet absorbent are mixed, and has higher safety
without causing any skin trouble.
Experiment 3 Capability to Preserved Humidity
Change of skin conductance in a group consisting of 15 men and 15 women
were measured under the environmental condition of the room temperature of
25.degree. C. and the relative humidity of 50%. The skin lotion produced
in Experiment 1 was applied to an arm of each member of the group, and the
skin conductance of the arm skin was measured in 24 hours after the
treatment. The capability to preserve humidity was determined according to
the increase ratio. Result of the determination were as follows.
##EQU1##
The results are shown in Table 3. l
TABLE 3
______________________________________
APPLIED SECTION APPLIED SECTION
IN EXAMPLE 1 IN CONTROL 1
______________________________________
.largecircle.
21 6
.DELTA. 9 8
.times. 0 16
______________________________________
From the results as described above, it was turned out that the external
preparation for skin with the benzophenone derivative according to the
present invention mixed therein is more excellent in its capability to
preserve humidity than the external preparation with the prior types of
water soluble ultraviolet absorbent.
Embodiment 4 2-Hydroxy 4-(2-maltoxyethoxy) benzophenone
1 g of 2,4-dihydroxy benzophenone was added to and dissolved in 7 g of
ethylbromohydrin, 37 mg of sodium hydroxide and 0.25 g of purified water.
The solution was heated to 100.degree. C. and stirred and then cooled to
90.degree. C. Furthermore, 224 mg of sodium hydroxide was added to the
mixture. The mixture was heated and stirred for 2 hours, and then cooled.
The resultant was extracted with chloroform, washed with water, and
condensed by removing the water. The product was purified using the silica
gel chromatography (Toluene: Methylethyl ketone), and 1.1 g of 2-hydroxy
4-(2-hydroxyethoxy) benzophenone was obtained.
Then, 100 mg of the product was dissolved in 1 ml of toluene, and 219 mg of
acetylmaltose and 10 mg of molybdoric acid were added. The resultant
product was heated and stirred for 30 minutes under the temperature of
100.degree. C. Then the reaction system was cooled by air to the room
temperature, extracted by toluene, and the extract was washed once with
purified water and 4 times with saturated saline, and the organic layer
was dried with sulfuric magnesium anhydride and condensed under reduced
pressure condition. The residual materials are purified according to the
silica gel chromatography (Hexan: Ethyl acetate), and 110 mg of acetylated
compound of 2-hydroxy 4-(2-maltosiloxyethoxy) benzophenone was obtained.
100 mg of this acetylated 2-hydroxy 4-(2-maltosiloxy) benzophenone was
dissolved in 3 ml of methanol, 0.3 ml of natorium methylate was added to
the mixture. The resultant mixture was stirred for 30 minutes under the
room temperature, neutralized by an ion-exchange resin (such as, for
instance, Umberlite IR 120B supplied from Organo Kogyo or UBK 530 from
Mitsubishi Kasei), and the resin was removed by filtering. The reactant
liquid was condensed under reduced pressure condition, and 2-hydroxy
4-(2-maltosiloxyethoxy) benzophenone was obtained. The resultant 2-hydroxy
4-(2-maltosiloxyethoxy) benzophenone was analyzed according to the methods
(1) to (6).
(1) Infrared absorption spectroscopy
Measurement was made by using the IRA-1 infrared absorption spectrometer
supplied from Nihon Bunko Kabushiki Kaisha with the KBr disk method, and
absorption due to stretching vibration of the hydroxyl group at 3400
cm.sup.-1, stretching vibration of the 2-maltosiloxyethoxy group at 2920
cm.sup.-1 and stretching vibration of the carbonyl group at 1630 cm.sup.-1
were observed.
The results are shown in FIG. 9.
(2) .sup.13 C-NMR spectroscopy
Measurement was made by using CD.sub.3 OD as a solvent with JOEL GX-400
from Nippon Denshi Kabushiki Kaisha at room temperature, and signal were
observed at .delta.201 ppm, 167 ppm, 167 ppm, 140 ppm, 136 ppm, 133 ppm,
130 ppm, 129 ppm, 115 ppm, 108 ppm, 105 ppm, 103 ppm, 103 ppm, 81 ppm, 78
ppm, 77 ppm, 75 ppm, 75 ppm, 75 ppm, 74 ppm, 74 ppm, 72 ppm, 69 ppm, 69
ppm, 63 ppm, and 62 ppm.
The resultant are shown in FIG. 10.
(3) .sup.1 H-NMR spectroscopy
Measurement was made by using CD.sub.3 OD as a solvent with JOEL GX-400
supplied from Nippon Denshi Kabushiki Kaisha under room temperature, and
signals were observed at .delta.7.53-7.38 ppm, 6.46 to 6.39, and 4.72 to
3.11.
The resultant are shown in FIG. 11.
(4) Ultraviolet ray absorption spectroscopy
Measurement was made by using the UVIDEC 610 C ultraviolet absorption
spectrometer from Nihon Bunko Kabushiki Kaisha with methanol as a solvent,
and the peak absorption was observed at 287.6 nm and 324.6 nm.
The results was shown in FIG. 12.
(5) Melting point
Measuring was carried out by using the melting point measuring device based
on a capillary system from Arthur H. Thoms Company, and the material was
melted in the temperature range of 92.degree. to 110.degree. C., but a
clear melting pint was not shown.
(6) Water solubility
20 weight % or more was dissolved in water.
Embodiment 5 2-hydroxy 4-(2-glucosiloxyethoxy) benzophenone
100 mg of the 2-hydroxy 4-(2-hydroxyethoxy) benzophenone synthesized in the
Embodiment 4 was dissolved in 2 ml of toluene, 136 mg of acetylglucose was
added to the mixture, and the resultant mixture was heated to 100.degree.
C., 50 mg of molybdoric acid was added to it, and the resultant mixture
was heated and stirred for 30 minutes under the temperature of 100.degree.
C. The reaction system was air cooled to the room temperature, extracted
by toluene, washed once with purified water and 4 times with saturated
saline, and the organic layer was dried with sulfuric magnesium anhydride
and was condensed under reduced pressure condition. The residual materials
were purified according to the silica gel chromatography (Hexan:
Ethylacetate), and 189 mg of acetylide of 2-hydroxy
4-(2-glycosiloxyethoxy) benzophenone was obtained.
189 mg of the acetylated 2-hydroxy 4-(2-maltosiloxyethoxy) benzophenone was
dissolved in 6 ml of methanol, 0.6 ml of the sodium methylate was added to
it, and the resultant mixture was stirred for 30 minutes under room
temperature, neutralized by an ion-exchange resin (such as, for instance,
Umbarlite IR120B from Organo Kogyo, or UBK 530 from Mitsubishi Kasei), the
resin was removed by filtering, the reactant liquid was condensed under
reduced pressure condition, and 2-hydroxy 4-(2-glucosiloxyethoxy)
benzophenone was obtained. The obtained 2-hydroxy 4-(2-glucosiloxyethoxy)
benzophenone was analyzed according to the method (1) to (6) described
below.
(1) Infrared absorption spectroscopy
Measurement was made by using the IRA-1 infrared absorption spectrometer
supplied from Nihon Bunko Kabushiki Kaisha with the KBr disk method, and
absorption due to stretching vibration of the hydroxyl group at 3400
cm.sup.-1, stretching vibration of the 2-glucosiloxyethoxy group at 2930
cm.sup.-1, and stretching vibration of the carbonyl group at 1630
cm.sup.-1 were observed.
The results are shown in FIG. 13.
(2) .sup.13 C-NMR spectroscopy
Measurement was made by using CD.sub.3 OD as a solvent with JOEL GX-400
from Nippon Denshi Kabushiki Kaisha at room temperature, and signal were
observed at .delta.201 ppm, 167 ppm, 167 ppm, 140 ppm, 136 ppm, 133 ppm,
130 ppm, 129 ppm, 114 ppm, 109 ppm, 108 ppm, 104 ppm, 103 ppm, 78 ppm, 75
ppm, 72 ppm, 69 ppm, 69 ppm, and 62 ppm.
The resultant are shown in FIG. 14.
(3) .sup.1 H-NMR spectroscopy
Measurement was made by using CD.sub.3 OD as a solvent with JOEL GX-400
supplied from Nippon Denshi Kabushiki Kaisha, and signals were observed at
.delta.7.52-7.38 ppm, 6.45 to 6.39, and 4.28 to 3.10.
The resultant are shown in FIG. 15.
(4) Ultraviolet ray absorption spectroscopy
Measurement was made by using the UVIDEC 610 C ultraviolet absorption
spectrometer from Nihon Bunko Kabushiki Kaisha with methanol as a solvent,
and the peak absorption was observed at 286.9 nm and 324.3 nm.
The results was shown in FIG. 16.
(5) Melting point
The compound absorbs much humidity, and measurement could not be carried
out.
(6) Water solubility
The compound was dissolved in water by around 10 weight %.
Embodiment 6 2-hydroxy 4-(3-maltosiloxypropyroxy) benzophenone
1 g of 2,4-dihydroxy benzophenone was dissolved with 7.78 g of
1-bromopropanol, 40 mg of sodium hydroxide, and 0.1 ml of purified water.
The mixture was heated to 100.degree. C. and stirred, and was cooled to
90.degree. C. Furthermore 220 mg of sodium hydroxide was added. The
mixture was heated and stirred for 4 hours, and then air cooled, extracted
by chloroform, washed with water, and then dried and condensed. The
product was purified by using the silica gel column chromatography
(Toluene: Methylethyl ketone), and 1.01 g of 2-hydroxy
4-(3-hydroxypropyroxy) benzophenone was obtained (Yield: 80%).
1.14 g of octaacetyl maltose was added to 460 mg of 2-hydroxy
4-(3-hydroxypropyroxy) benzophenone, and the mixture was dissolved in 10
ml of toluene, and heated to 90.degree. C., and then a catalystic level of
molybdoric acid was added to it. The mixture was heated and stirred for 30
minutes and then air cooled, extracted with 100 ml of toluene, and washed
with saturated sodium bicarbonate water. After dried and condensed, the
product was purified by the silica gel chromatography (Toluene:
Methylethyl ketone), and 880 mg of acetylide of 2-hydroxy
4-(3-maltosiloxypropyroxy) benzophenone was obtained (Yield: 60%).
880 mg of the acetylide of 2-hydroxy 4-(3-maltosiloxypropyroxy)
benzophenone was dissolved in 20 ml of methanol, sodium methoxide was
added. The mixture was stirred for 30 minutes and then neutralized by
acidic resin, filtered and condensed and 565 mg of 2-hydroxy
4-(3-maltosiloxypropyroxy) benzophenone was obtained (Yield: 100%).
The 2-hydroxy 4-(3-maltosiloxypropyroxy) benzophenone was confirmed
according to the methods (1) to (6) described below.
(1) Infrared absorption spectroscopy
Measurement was made by using the IRA-1 infrared absorption spectrometer
supplied from Nihon Bunko Kabushiki Kaisha with the KBr disk method, and
absorption due to stretching vibration of the hydroxyl group at 3400
cm.sup.-1, stretching vibration of the 3-maltosiloxy group at 2930
cm.sup.-1, and stretching vibration of the carbonyl group at 1626
cm.sup.-1 were observed.
The results are shown in FIG. 17.
(2) .sup.13 C-NMR spectroscopy
Measurement was made by using CD.sub.3 OD as a solvent with JOEL GX-400
from Nippon Denshi Kabushiki Kaisha under room temperature, and signal
were observed at .delta.201 ppm, 167 ppm, 167 ppm, 140 ppm, 136 ppm, 133
ppm, 130 ppm, 129 ppm, 114 ppm, 109 ppm, 104 ppm, 103 ppm, 81 ppm, 78 ppm,
76 ppm, 75 ppm, 75 ppm, 74 ppm, 71 ppm, 67 ppm, 67 ppm, 63 ppm, 62 ppm,
and 30 ppm.
The resultant are shown in FIG. 18.
(3) .sup.1 H-NMR spectroscopy
Measurement was made by using CD.sub.3 OD as a solvent with JOEL GX-400
supplied from Nippon Denshi Kabushiki Kaisha under room temperature, and
signals were observed at .delta.7.55 ppm, 7.50 ppm, 7.43 ppm, 6.56 ppm,
6.50 ppm, 6.44 ppm, and in a range from 5.22 ppm to 1.9 ppm.
The resultant are shown in FIG. 19.
(4) Ultraviolet ray absorption spectroscopy
Measurement was made by using the UVIDEC 610 C ultraviolet ray absorption
spectrometer from Nihon Bunko Kabushiki Kaisha with methanol as a solvent,
and the peak absorption was observed at 289.4 nm and 324.1 nm.
The results was shown in FIG. 20.
(5) Melting point
Measurement was made by using the melting point measuring device based on a
capillary system developed by Arthur H. Thomas Company, and the product
was melted in temperature range from 77.degree. to 87.degree. C., but a
clear melting point was not shown.
(6) Water solubility
The compound was dissolved in water by around 20 weight % or more.
Experiment 4 Production of Skin Lotion
According to the formulation as shown in table 4, a skin lotion in which
the benzophenone derivative was mixed, and a skin lotion in which
2-hydroxy-4-methoxy-5-sulfoxisonium benzophenone as a control ware
produced.
TABLE 4
______________________________________
COMPONENT EXAMPLE 2 CONTROL 1
______________________________________
A (ALCOHOL PHASE)
Ethanol 5.0 5.0
POE oleil alcohol ether
2.0 2.0
Perfume q.s. q.s.
B (AQUEOUS PHASE)
1,3-butylene glycerol
5.0 5.0
Benzophenone derivative
8.0 --
(Embodiment 4)
2-hydroxy-4-methoxy-sulfoxonium
-- 8.0
benzophenone
Triethanol amine 0.1 0.1
Carboxy vinyl polymer
0.15 0.15
Purified water Residual Residual
______________________________________
Alcohol phase A was added to aqueous phase B, and a perfume was made water
soluble to obtain a skin lotion.
In example 2, an excellent skin lotion which is transparent and viscosity
without any specific color, while in control 2 a lotion which was yellow
color and has no viscosity was obtained.
Experiment 5 Test for Anti-suntan Material
Field test were carried out in a sea beach using 2 types of skin lotion
produced in Experiment 4. In the experiment, the sample were applied to
right and left halves of each member of a group consisting of 20 men and
20 women. A degree of sun burning was determined. The criteria for the
determination of a degree of burning by sunlight and other condition are
the same as those in Experiment 2 above.
The results are shown in Table 5.
TABLE 5
______________________________________
APPLIED APPLIED
SECTION IN
SECTION IN
EXAMPLE 2 CONTROL 2
______________________________________
.largecircle.
39 6
.DELTA. 1 15
.times. 0 19
NUMBER OF NONE ITCH 8 CASES
SKIN TROUBLE ERUPTION 2 CASES
CASES
______________________________________
From the results as described above, the external preparation for skin in
which the benzophenone derivative is mixed is more effective for
protection from ultraviolet rays than that in which the prior types of
water soluble ultraviolet absorbent are mixed, and has higher safety
without causing any skin trouble.
Experiment 6 Capability to Preserved Humidity
The capability of the product to preserve humidity was tested according to
the same procedure as that in experiment 3 above.
The results are as shown in Table 6.
TABLE 6
______________________________________
APPLIED SECTION APPLIED SECTION
IN EXAMPLE 2 IN CONTROL 2
______________________________________
.largecircle.
26 6
.DELTA. 4 8
.times. 0 16
______________________________________
From the results as described above, it was turned out that the external
preparation for skin with the benzophenone derivative according to the
present invention mixed therein is more excellent in its capability to
preserve humidity than the external preparation with the prior types of
water soluble ultraviolet absorbent.
Description is made for examples of mixing in the external preparation for
skin according to the present invention. It should be noted that each
external preparations showed an excellent effect for preventing
ultraviolet rays.
______________________________________
Embodiment 7 Cream
______________________________________
A. Oily phase
Stearic acid 10.0
Stearyl alcohol 4.0
Stearic acid monoglycerin 8.0
Vitamin E acetate 0.5
Perfume 0.4
Ethyl paraben 0.1
Butyl paraben 0.1
Propyl paraben 0.1
B. Aqueous phase
Propylene glycol 8.0
Glycerin 2.0
1-(4-benzoyl-3-hydroxy phenyl) glycerol maltitolether
6.0
Potassium hydroxide 0.4
Trisodium edetate 0.05
Purified water Residual
______________________________________
Production method
The oily fraction A and the aqueous fraction B are heated to 70.degree. C.
and completely dissolved. Then phase A is added to phase B, and the
mixture is emulsified by a emulsifier. Then the emulsion is cooled by a
heat exchanger and the cream is obtained.
______________________________________
Embodiment 8 Cream
______________________________________
A. Oily phase
Cetanol 4.0
Vaseline 7.0
Isopropyl milistate 8.0
Squalane 12.0
Dimethyl polysiloxane 3.0
Stearic acid monoglycerin ester
2.2
POE(20) solbitane monostearate
0.5
Glycyrrhyzin acid stearate 0.1
BHT 0.02
Ethylparaben 0.1
Butylparaben 0.1
Propylparaben 0.1
B. Aqueous phase
1,3 butylene glycol 7.0
Disodium edetate 0.07
Phenoxyethanol 0.2
L-ascorbic acid phosphoric acid ester magnesium salt
3.0
Polyacrylic acid alkyl ester
1.0
1-(4-benzoylphenyl) glycerol maltitolether
8.0
Purified water Residual
______________________________________
Production method
The cream was obtained according to the procedure as in the Embodiment 7.
______________________________________
Embodiment 9 Milky Lotion
______________________________________
A. Oily phase
Oleylorate 3.0
Vaseline 7.0
Squalane 5.0
Sorbitane-sesqui-oleic acid ester
0.8
Polyoxyethylene oleil ether (20 E.O.)
1.2
1-(4-benzoyl-3-hydroxy phenyl) glycerol solbitol ether
3.0
Methylparaben 0.1
Perfume 0.12
B. Aqueous phase
Dipropylenglycol 5.0
Ethanol 3.0
Carboxy vinyl polymer 0.17
Sodium hyrluronate 0.01
Polyacrylic alkyl ester 1.0
1-(4-benzoyl-3-hydroxy phenyl) glycerol sugar ether
4.0
Potassium hydroxide 0.08
Hexametalic acid sodium 0.05
Purified water Residual
______________________________________
Production method
The milky lotion was obtained according to the same procedure as in the
Embodiment 7.
______________________________________
Embodiment 10 Cream
______________________________________
A. Oily phase
Behenyl alcohol 0.5
12-hydroxy stearic acid cholestanol ester
2.0
Squalane 7.0
Jojoba oil 5.0
Self-emulsifying type monostearic acid glycerin
2.5
Polyoxyethylene sorbithane 1.5
monestearic acid ester(2OEO)
2-hydroxy-4-methoxy benzophenone
3.0
Ethylparaben 0.2
Butylparaben 0.1
Propylparaben 0.1
B. Aqueous phase
Propylene glycol 5.0
Sodium edetate 0.08
Glycerin 5.0
Beegum (Montmorillonite) 3.0
Potassium hydroxide 3.3
1-(4-benzoyl-3-hydroxyphenyl) glycerol
8.0
maltotriol ether
Purified water Residual
______________________________________
Production method
The cream was obtained according to the same procedure as in the Embodiment
7.
______________________________________
Embodiment 11 Skin Lotion with powder
______________________________________
A. Oily phase
Ethanol 8.0
POE(60) glyceril monoisostearate
2.0
L-menthol 0.1
Campher 0.1
Methylparaben 0.2
Perfume q.s.
B. Aqueous phase
Glycerin 3.5
1-(4-benzoyl phenyl) glycerol maltotriolether
4.0
Zinc 1.5
Kaolin 0.5
12-hydroxy stearic acid cholestanol ester
2.0
Squalane 7.0
Jojoba oil 5.0
Self-emulsifying type monostearic acid glycerin
2.5
Polyoxyethylene sorbithane monestearic
1.5
acid ester(2OEO)
2-hydroxy-4-methoxy benzophenone
3.0
Ethylparaben 0.2
Butylparaben 0.1
Propylparaben 0.1
B. Aqueous phase
Propylene glycol 5.0
Sodium edetate 0.08
Glycerin 5.0
Beegum (Montmorillonite) 3.0
Potassium hydroxide 3.3
2,2',4'-trihydroxy-4(2-maltosiloxyethoxy)
8.0
benzophenone
Purified water Residual
______________________________________
Production method
The cream was obtained according to the same procedure as in the Embodiment
7.
______________________________________
Embodiment 16 Skin Lotion with powder
______________________________________
A. Oily phase
Ethanol 8.0
POE(60) glyceril monoisostearate
2.0
L-menthol 0.1
Campher 0.1
Bentonite 0.3
Sodium hexamethalate 0.03
Purified water Residual
______________________________________
Production method
The skin lotion was obtained according to the same procedure as that in
Embodiment 7.
______________________________________
Embodiment 12 Cream
______________________________________
A. Oily phase
Stearic acid 10.0
Stearyl alcohol 4.0
Stearic acid monoglycerin 8.0
Vitamin E acetate 0.5
Perfume 0.4
Ethyl paraben 0.1
Butyl paraben 0.1
Propyl paraben 0.1
B. Aqueous phase
Propylene glycol 8.0
Glycerin 2.0
2-hydroxy 4-(2-maltosiloxyethoxy) Benzophenone
8.0
Potassium hydroxide 0.4
Trisodium edetate 0.05
Purified water Residual
______________________________________
Production method
The cream was obtained according to the same procedure as in the Embodiment
7.
______________________________________
Embodiment 13 Cream
______________________________________
A. Oily phase
Cetanol 4.0
Vaseline 7.0
Isopropyl milistate 8.0
Squalane 12.0
Dimethyl polysiloxane 3.0
Stearic acid monoglycerin ester
2.2
POE(20) solbitane monostearate
0.5
Glycyrrhyzin acid stearate 0.1
BHT 0.02
Ethylparaben 0.1
Butylparaben 0.1
Propylparaben 0.1
B. Aqueous phase
1,3 butylene glycol 7.0
Disodium edetate 0.07
Phenoxyethanol 0.2
L-ascorbic acid phosphoric acid ester magnesium salt
3.0
Polyacrylic acid alkyl ester
1.0
2-hydroxy-4-(2-glyceroilethoxy) benzophenone
8.0
Purified water Residual
______________________________________
Production method
The cream was obtained according to the procedure as in the Embodiment 7.
______________________________________
Embodiment 14 Milky Lotion
______________________________________
A. Oily phase
Oleylorate 3.0
Vaseline 7.0
Squalane 5.0
Sorbitane-sesqui-oleic acid ester
0.8
Polyoxyethylene oleyl ether (20 E.O.)
1.2
Di-p-methoxy cinnamic acid glycerol
3.0
Methylparaben 0.1
Perfume 0.12
B. Aqueous phase
Dipropylenglycol 5.0
Ethanol 3.0
Carboxy vinyl polymer 0.17
Sodium hyrluronate 0.01
Polyacrylic alkyl ester 1.0
2,2'-dihydroxy 4-(2-maltosiloxyethoxy) benzophenone
4.0
Potassium hydroxide 0.08
Hexametalic acid sodium 0.05
Purified water Residual
______________________________________
Production method
The milky lotion was obtained according to the same procedure as in the
Embodiment 7.
______________________________________
Embodiment 15 Cream
______________________________________
A. Oily phase
Behenyl alcohol 0.5
Methylparaben 0.2
Perfume q.s.
B. Aqueous phase
Glycerin 3.5
2-hydroxy-4(3-maltosiloxybuthoxy) benzophenone
4.0
Zinc 1.5
Kaolin 0.5
Bentonite 0.3
Sodium hexamethalate 0.03
Purified water Residual
______________________________________
Production method
The skin lotion was obtained according to the same procedure as that in
Embodiment 7.
As described above, the benzophenone derivatives according to the present
invention have excellent capability to absorb ultraviolet rays as well as
high compatibility with polar solvent.
Also, the external preparation for skin in which the materials are mixed
can be mixed in a polar base, which insures wide availability for
industrial purpose.
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